Summary Cell-based regenerative therapy holds tremendous promise to alleviate, if not cure, degenerative diseases such as diabetes, heart failure, and Parkinson's disease. The availability of human pluripotent cells such as embryonic stem (ES) cells or the recently described induced pluripotent stem (iPS) cells have raised the prospect that differentiated progenies from these cells may be purified and transplanted in a clinical setting. Recent preclinical studies using cardiomyocytes derived from in vitro differentiated ES cells to regenerated damaged heart muscle have revealed significant difficulty in engraftment, expansion, and functional integration of the transplanted cells. These challenges are being addressed in different ways including tissue-engineering approaches; however, recapitulation of native tissue architecture may be extremely difficult given the variety of cell types involved. One possibility that these challenges may be overcome is if replacement tissue or the entire organ can be generated via normal developmental mechanisms in non-human species. This would ensure proper cellular architecture, vascularity, and most importantly, function. Cross-specie immune tolerance during embryonic development is a biological feature that has been well described in the literature. Little work has been done to show the developmental potential or limitations when pluripotent cells derived from one specie (e.g. rat or pig) are transferred into the developing blastocyst of another specie (e.g. mice or sheep), a procedure that has generated hundreds of genetically targeted mice thus far. Developmental compatibility is expected to correlate with the relatedness between species, but the extent of cross-specie tolerance is largely unknown. By exploring the developmental potential of inter- specie chimerism, one may be able to assess, in the future, the feasibility of deriving replacement tissues using pluripotent stem cell such as iPS cells from human into genetically engineered non-human primates or large animals. Having an accessible supply of animal derived, genetically matched, human tissue for transplantation would truly herald the dawning of the era of regenerative medicine.